Real-World Effectiveness of Single-Inhaler Triple Therapy for COPD: Impact of Diabetes Comorbidity

Abstract

Background

Type 2 diabetes is a frequent comorbidity in chronic obstructive pulmonary disease (COPD) patients, with the GOLD treatment recommendations asserting that the presence of diabetes be disregarded in the choice of treatment.

Methods

In a cohort of COPD patients with frequent exacerbations, initiators of single-inhaler triple therapy or dual bronchodilators were compared on the incidence of COPD exacerbation and pneumonia over one year, adjusted by propensity score weighting and stratified by type 2 diabetes.

Results

The COPD cohort included 1,114 initiators of triple inhalers and 4,233 of dual bronchodilators (28% with type 2 diabetes). The adjusted hazard ratio (HR) of exacerbation with triple therapy was 1.04 (95% CI: 0.86–1.25) among COPD patients with type 2 diabetes and 0.74 (0.65–0.85) in those without. The incidence of severe pneumonia was elevated with triple therapy among patients with type 2 diabetes (HR 1.77; 1.14–2.75).

Conclusion

Triple therapy in COPD is effective among those without, but not those with, type 2 diabetes. Future therapeutic trials in COPD should consider diabetes comorbidity.

TWITTER SUMMARY

Triple therapy for frequent COPD exacerbators is effective in patients without type 2 diabetes but not in those with type 2 diabetes. The impact of comorbidities should be considered in future COPD therapeutic trials.

Keywords:

• Cohort studies
• COPD exacerbation
• multimorbidity
• propensity scores
• real-world evidence

Introduction

Chronic obstructive pulmonary disease (COPD) typically affects people over the age of 40 whose lungs have been exposed to continuous damage, usually from smoking. Recommendations for the treatment of COPD increasingly acknowledge the importance of comorbidity in managing the disease [1]. A frequent comorbidity in patients with COPD is type 2 diabetes, with a prevalence varying from 10.2 to 45.0%, reported across 20 studies [2]. In two large trials of single-inhaler triple therapy in COPD patients, this prevalence was 15% and 18%, respectively [3,4]. Moreover, type 2 diabetes is among the comorbidities associated with poor outcomes in COPD patients, including higher mortality [5]. The latest edition of the Global Initiative for Chronic Obstructive Lung Disease (GOLD) report recommends, in the absence of data, that the two conditions be treated independently, as “the presence of comorbidities should not alter COPD treatment” [1].

In the most recent treatment recommendations, single-inhaler dual bronchodilators, that combine long-acting beta₂-agonists (LABAs) and muscarinic antagonists (LAMAs), are recommended as first-line pharmacological treatment for patients with COPD [1]. For those patients with a history of COPD exacerbations and eosinophilia, the recommendation is to use single-inhaler triple therapy, which combines a LAMA, a LABA and an inhaled corticosteroid (ICS). While these recommendations suggest that the treatment of COPD should not be affected by the presence of type 2 diabetes, no studies have evaluated this proposition that COPD treatments apply equally to patients with and without this comorbidity.

We use data from an observational study, designed to emulate a trial in real-world clinical practice, to assess whether the effectiveness of single-inhaler triple therapy compared with dual bronchodilators on major outcomes is affected by coexisting type 2 diabetes.

Methods

The study cohort has been described in detail [6]. It was identified from the Clinical Practice Research Datalink (CPRD), a primary care database from the United Kingdom (UK) that contains primary care medical records for over 50 million people enrolled in more than 1800 general practices, spanning over 30 years. The CPRD includes patient information on demographic and lifestyle factors, diagnoses, prescriptions and is linked to hospitalizations records.

The study employed a new-user cohort approach, designed to emulate a trial in real-world clinical practice. The subjects thus entered the study cohort on the date of their very first prescription for a single-inhaler triple (LAMA-LABA-ICS) or for a single-inhaler dual bronchodilator (LAMA-LABA) after 15 September 2017, the date when the first triple inhaler became available in the UK [6]. All subjects needed a prior diagnosis of COPD and a baseline year of medical history before entry. Subjects also needed at least two exacerbations in the baseline year, the indication for triple therapy. Moreover, subjects who received ICS in the baseline year prior to cohort entry were excluded to avoid exposure misclassification of the LAMA-LABA-arm.

Study subjects were followed for one year from the date of treatment initiation, or until discontinuation of the initial inhaler. The primary effectiveness outcome was the first moderate or severe COPD exacerbation to occur after cohort entry. A severe exacerbation was defined as a hospitalization for COPD and a moderate exacerbation by a new prescription for prednisolone. The safety outcome was the first severe pneumonia, defined by hospitalization for community-acquired pneumonia.

Propensity scores of treatment initiation were calculated using several covariates, including demographics, lifestyle, markers of COPD severity, and co-morbidities. Age, sex, body mass index (BMI), smoking status and alcohol abuse were measured at or prior to cohort entry. COPD severity was assessed by the number of prior COPD exacerbations, and frequency of use other respiratory drugs, including short-acting inhaled beta-agonists and anticholinergics, methylxanthines, and antibiotics used for respiratory conditions, all measured during the one-year baseline period. The most recent measures of dyspnea, forced expiratory volume (FEV₁) and blood eosinophil count prior to cohort entry, were identified. Baseline co-morbidity in the year prior to cohort entry was measured using clinical diagnoses, hospitalizations, and prescriptions.

Fine stratification weights were computed using 100 strata created by the propensity score distributions to achieve comparable treatment groups. Weighted Cox proportional hazard models, adjusted by fine stratification weights, were used to estimate hazard ratios. These analyses were stratified by the presence of type 2 diabetes at treatment initiation.

Results

The study cohort included 1,114 frequent exacerbators with COPD who initiated triple inhalers and 4,233 who initiated dual inhalers, including 28% with type 2 diabetes. After propensity score weighing, the two treatment arms were comparable on all covariates (standardized differences <0.10). The subjects with type 2 diabetes comorbidity were 70 years of age at cohort entry, 38% were female, and 43% were obese. They were treated in the baseline year with metformin (43%), sulfonylureas (14%), insulin (14%), DPP4 inhibitors (13%), SGLT2 inhibitors (4%), and GLP1 agonists (4%).

The hazard ratio of a moderate or severe exacerbation with triple therapy compared with a dual inhaler was 1.04 (95% CI: 0.86–1.25) in the COPD patients with type 2 diabetes and 0.74 (95% CI: 0.65–0.85) in the COPD patients without diabetes (Figure 1). The incidence of severe pneumonia requiring hospitalization was elevated with triple therapy among patients with type 2 diabetes (HR 1.77: 95% CI: 1.14–2.75), but not significantly so in those without diabetes (HR 1.19: 95% CI: 0.83–1.71) (Figure 1).

Figure 1. Hazard ratio of moderate or severe COPD exacerbation and of severe pneumonia comparing single-inhaler triple therapy with single-inhaler LAMA-LABA dual bronchodilators in COPD patients with a history of multiple exacerbations, in the first year after treatment initiation, stratified by the presence of type 2 diabetes comorbidity.

Discussion

Our analyses suggest that the presence of type 2 diabetes alongside COPD may alter the effectiveness of therapy. We found that treatment of COPD with single-inhaler triple therapy, among patients with frequent exacerbations, is more effective than with a dual bronchodilator at reducing the risk of an exacerbation, but only among patients without type 2 diabetes. For those patients who also have type 2 diabetes, triple therapy did not reduce the incidence of an exacerbation compared with a dual bronchodilator.

The comorbidity of type 2 diabetes and COPD is considerable, with an elevated prevalence of type 2 diabetes among patients with COPD [2]. Moreover, type 2 diabetes is among the leading comorbidities associated with poor outcomes and higher mortality in COPD [5]. Some hypotheses suggest the role of obesity as a common risk factor in both diseases, based on population and genetic studies, while others suggest a role for inflammation and exposure to cigarette smoke [7, 8]. However, no study has examined the impact of type 2 diabetes on altering the effectiveness of treatments for COPD.

Various mechanisms might influence the effectiveness of triple therapy with type 2 diabetes. Treatment with triple therapy could be affected by the hyperglycemia-related impairment of the immune system [9]. Also, neutrophilic inflammation plays an important role in type 2 diabetes and this may spillover into the lungs potentially reducing the benefit of the ICS component of triple therapy targeting eosinophilic inflammation [10]. Finally, the rate of severe pneumonia associated with triple therapy was substantially higher among patients with type 2 diabetes such that misclassification of pneumonia as a COPD exacerbation may mask any benefit on exacerbations.

Strengths of our real-world observational study include the use of validated diagnoses to identify COPD, comorbidities, and outcomes from primary care and hospital records [6]. The large size of the base cohort allowed restriction to patients with a history of prior exacerbations and stratification by type 2 diabetes comorbidity. Our study is limited by relying on medication prescriptions, which cannot ensure compliance. While large, our study size was insufficient to further stratify by blood eosinophils count (>300cells/µl) as per by GOLD recommendations. Residual confounding is also a limitation.

While the GOLD recommendations for the treatment of COPD recognize the importance of comorbidity in managing the disease, the advice is to treat the different conditions independently, using the respective guidelines [1]. Our study suggests, using the example of type 2 diabetes, that the effectiveness of a treatment for COPD may be affected by the presence of a comorbidity. Future COPD therapeutic trials should consider the effects of comorbidities, which could become important in developing precision medicine approaches for COPD management.

Acknowledgements

This study is not funded. Pr. Suissa is the recipient of the Distinguished James McGill Professorship award. All authors contributed equally to the research and manuscript. Pr Suissa is the guarantor of the content of the manuscript, including the data and analysis.

Data sharing statement

This study is based in part on data from the Clinical Practice Research Datalink obtained under license from the UK Medicines and Healthcare products Regulatory Agency. The data are provided by patients and collected by the UK National Health Service as part of their care and support. Because electronic health records are classified as “sensitive data” by the UK Data Protection Act, information governance restrictions (to protect patient confidentiality) prevent data sharing via public deposition. Data are available with approval through the individual constituent entities controlling access to the data. Specifically, the primary care data can be requested via application to the Clinical Practice Research Datalink (https://www.cprd.com).

Disclosure statement

S. Suissa attended scientific advisory committee meetings or received speaking fees from AstraZeneca, Atara, Boehringer-Ingelheim, Bristol-Myers-Squibb, Merck, Novartis, Panalgo, Pfizer and Seqirus. SET and PE have no conflicts.

Additional information

Funding

The author(s) reported there is no funding associated with the work featured in this article.